Oncogenic KRAS Reduces Expression of FGF21 in Acinar Cells to Promote Pancreatic Tumorigenesis in Mice on a High-Fat Diet

Yongde Luo, Yaying Yang, Muyun Liu, Dan Wang, Feng Wang, Yawei Bi, Juntao Ji, Suyun Li, Yan Liu, Rong Chen, Haojie Huang, Xiaojie Wang, Agnieszka K. Swidnicka-Siergiejko, Tobias Janowitz, Semir Beyaz, Guoqiang Wang, Sulan Xu, Agnieszka B. Bialkowska, Catherine K. Luo, Christoph L. PinGuang Liang, Xiongbin Lu, Maoxin Wu, Kenneth R. Shroyer, Robert A. Wolff, William Plunkett, Baoan Ji, Zhaoshen Li, Ellen Li, Xiaokun Li, Vincent W. Yang, Craig D. Logsdon, James L. Abbruzzese, Weiqin Lu

Research output: Contribution to journalArticle

Abstract

Background & Aims: Obesity is a risk factor for pancreatic cancer. In mice, a high-fat diet (HFD) and expression of oncogenic KRAS lead to development of invasive pancreatic ductal adenocarcinoma (PDAC) by unknown mechanisms. We investigated how oncogenic KRAS regulates the expression of fibroblast growth factor 21, FGF21, a metabolic regulator that prevents obesity, and the effects of recombinant human FGF21 (rhFGF21) on pancreatic tumorigenesis. Methods: We performed immunohistochemical analyses of FGF21 levels in human pancreatic tissue arrays, comprising 59 PDAC specimens and 45 nontumor tissues. We also studied mice with tamoxifen-inducible expression of oncogenic KRAS in acinar cells (KrasG12D/+ mice) and fElasCreERT mice (controls). KrasG12D/+ mice were placed on an HFD or regular chow diet (control) and given injections of rhFGF21 or vehicle; pancreata were collected and analyzed by histology, immunoblots, quantitative polymerase chain reaction, and immunohistochemistry. We measured markers of inflammation in the pancreas, liver, and adipose tissue. Activity of RAS was measured based on the amount of bound guanosine triphosphate. Results: Pancreatic tissues of mice expressed high levels of FGF21 compared with liver tissues. FGF21 and its receptor proteins were expressed by acinar cells. Acinar cells that expressed KrasG12D/+ had significantly lower expression of Fgf21 messenger RNA compared with acinar cells from control mice, partly due to down-regulation of PPARG expression—a transcription factor that activates Fgf21 transcription. Pancreata from KrasG12D/+ mice on a control diet and given injections of rhFGF21 had reduced pancreatic inflammation, infiltration by immune cells, and acinar-to-ductal metaplasia compared with mice given injections of vehicle. HFD-fed KrasG12D/+ mice given injections of vehicle accumulated abdominal fat, developed extensive inflammation, pancreatic cysts, and high-grade pancreatic intraepithelial neoplasias (PanINs); half the mice developed PDAC with liver metastases. HFD-fed KrasG12D/+ mice given injections of rhFGF21 had reduced accumulation of abdominal fat and pancreatic triglycerides, fewer pancreatic cysts, reduced systemic and pancreatic markers of inflammation, fewer PanINs, and longer survival—only approximately 12% of the mice developed PDACs, and none of the mice had metastases. Pancreata from HFD-fed KrasG12D/+ mice given injections of rhFGF21 had lower levels of active RAS than from mice given vehicle. Conclusions: Normal acinar cells from mice and humans express high levels of FGF21. In mice, acinar expression of oncogenic KRAS significantly reduces FGF21 expression. When these mice are placed on an HFD, they develop extensive inflammation, pancreatic cysts, PanINs, and PDACs, which are reduced by injection of FGF21. FGF21 also reduces the guanosine triphosphate binding capacity of RAS. FGF21 might be used in the prevention or treatment of pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)1413-1428.e11
JournalGastroenterology
Volume157
Issue number5
DOIs
StatePublished - Nov 2019

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Acinar Cells
High Fat Diet
Carcinogenesis
Pancreatic Cyst
Injections
Pancreas
Inflammation
fibroblast growth factor 21
Abdominal Fat
Adenocarcinoma
Guanosine Triphosphate
Pancreatic Neoplasms
Liver
Obesity
Neoplasm Metastasis
Diet
Neoplasms

Keywords

  • FGFR1
  • Gene Regulation
  • KLB
  • Signaling

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Oncogenic KRAS Reduces Expression of FGF21 in Acinar Cells to Promote Pancreatic Tumorigenesis in Mice on a High-Fat Diet. / Luo, Yongde; Yang, Yaying; Liu, Muyun; Wang, Dan; Wang, Feng; Bi, Yawei; Ji, Juntao; Li, Suyun; Liu, Yan; Chen, Rong; Huang, Haojie; Wang, Xiaojie; Swidnicka-Siergiejko, Agnieszka K.; Janowitz, Tobias; Beyaz, Semir; Wang, Guoqiang; Xu, Sulan; Bialkowska, Agnieszka B.; Luo, Catherine K.; Pin, Christoph L.; Liang, Guang; Lu, Xiongbin; Wu, Maoxin; Shroyer, Kenneth R.; Wolff, Robert A.; Plunkett, William; Ji, Baoan; Li, Zhaoshen; Li, Ellen; Li, Xiaokun; Yang, Vincent W.; Logsdon, Craig D.; Abbruzzese, James L.; Lu, Weiqin.

In: Gastroenterology, Vol. 157, No. 5, 11.2019, p. 1413-1428.e11.

Research output: Contribution to journalArticle

Luo, Y, Yang, Y, Liu, M, Wang, D, Wang, F, Bi, Y, Ji, J, Li, S, Liu, Y, Chen, R, Huang, H, Wang, X, Swidnicka-Siergiejko, AK, Janowitz, T, Beyaz, S, Wang, G, Xu, S, Bialkowska, AB, Luo, CK, Pin, CL, Liang, G, Lu, X, Wu, M, Shroyer, KR, Wolff, RA, Plunkett, W, Ji, B, Li, Z, Li, E, Li, X, Yang, VW, Logsdon, CD, Abbruzzese, JL & Lu, W 2019, 'Oncogenic KRAS Reduces Expression of FGF21 in Acinar Cells to Promote Pancreatic Tumorigenesis in Mice on a High-Fat Diet', Gastroenterology, vol. 157, no. 5, pp. 1413-1428.e11. https://doi.org/10.1053/j.gastro.2019.07.030
Luo, Yongde ; Yang, Yaying ; Liu, Muyun ; Wang, Dan ; Wang, Feng ; Bi, Yawei ; Ji, Juntao ; Li, Suyun ; Liu, Yan ; Chen, Rong ; Huang, Haojie ; Wang, Xiaojie ; Swidnicka-Siergiejko, Agnieszka K. ; Janowitz, Tobias ; Beyaz, Semir ; Wang, Guoqiang ; Xu, Sulan ; Bialkowska, Agnieszka B. ; Luo, Catherine K. ; Pin, Christoph L. ; Liang, Guang ; Lu, Xiongbin ; Wu, Maoxin ; Shroyer, Kenneth R. ; Wolff, Robert A. ; Plunkett, William ; Ji, Baoan ; Li, Zhaoshen ; Li, Ellen ; Li, Xiaokun ; Yang, Vincent W. ; Logsdon, Craig D. ; Abbruzzese, James L. ; Lu, Weiqin. / Oncogenic KRAS Reduces Expression of FGF21 in Acinar Cells to Promote Pancreatic Tumorigenesis in Mice on a High-Fat Diet. In: Gastroenterology. 2019 ; Vol. 157, No. 5. pp. 1413-1428.e11.
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title = "Oncogenic KRAS Reduces Expression of FGF21 in Acinar Cells to Promote Pancreatic Tumorigenesis in Mice on a High-Fat Diet",
abstract = "Background & Aims: Obesity is a risk factor for pancreatic cancer. In mice, a high-fat diet (HFD) and expression of oncogenic KRAS lead to development of invasive pancreatic ductal adenocarcinoma (PDAC) by unknown mechanisms. We investigated how oncogenic KRAS regulates the expression of fibroblast growth factor 21, FGF21, a metabolic regulator that prevents obesity, and the effects of recombinant human FGF21 (rhFGF21) on pancreatic tumorigenesis. Methods: We performed immunohistochemical analyses of FGF21 levels in human pancreatic tissue arrays, comprising 59 PDAC specimens and 45 nontumor tissues. We also studied mice with tamoxifen-inducible expression of oncogenic KRAS in acinar cells (KrasG12D/+ mice) and fElasCreERT mice (controls). KrasG12D/+ mice were placed on an HFD or regular chow diet (control) and given injections of rhFGF21 or vehicle; pancreata were collected and analyzed by histology, immunoblots, quantitative polymerase chain reaction, and immunohistochemistry. We measured markers of inflammation in the pancreas, liver, and adipose tissue. Activity of RAS was measured based on the amount of bound guanosine triphosphate. Results: Pancreatic tissues of mice expressed high levels of FGF21 compared with liver tissues. FGF21 and its receptor proteins were expressed by acinar cells. Acinar cells that expressed KrasG12D/+ had significantly lower expression of Fgf21 messenger RNA compared with acinar cells from control mice, partly due to down-regulation of PPARG expression—a transcription factor that activates Fgf21 transcription. Pancreata from KrasG12D/+ mice on a control diet and given injections of rhFGF21 had reduced pancreatic inflammation, infiltration by immune cells, and acinar-to-ductal metaplasia compared with mice given injections of vehicle. HFD-fed KrasG12D/+ mice given injections of vehicle accumulated abdominal fat, developed extensive inflammation, pancreatic cysts, and high-grade pancreatic intraepithelial neoplasias (PanINs); half the mice developed PDAC with liver metastases. HFD-fed KrasG12D/+ mice given injections of rhFGF21 had reduced accumulation of abdominal fat and pancreatic triglycerides, fewer pancreatic cysts, reduced systemic and pancreatic markers of inflammation, fewer PanINs, and longer survival—only approximately 12{\%} of the mice developed PDACs, and none of the mice had metastases. Pancreata from HFD-fed KrasG12D/+ mice given injections of rhFGF21 had lower levels of active RAS than from mice given vehicle. Conclusions: Normal acinar cells from mice and humans express high levels of FGF21. In mice, acinar expression of oncogenic KRAS significantly reduces FGF21 expression. When these mice are placed on an HFD, they develop extensive inflammation, pancreatic cysts, PanINs, and PDACs, which are reduced by injection of FGF21. FGF21 also reduces the guanosine triphosphate binding capacity of RAS. FGF21 might be used in the prevention or treatment of pancreatic cancer.",
keywords = "FGFR1, Gene Regulation, KLB, Signaling",
author = "Yongde Luo and Yaying Yang and Muyun Liu and Dan Wang and Feng Wang and Yawei Bi and Juntao Ji and Suyun Li and Yan Liu and Rong Chen and Haojie Huang and Xiaojie Wang and Swidnicka-Siergiejko, {Agnieszka K.} and Tobias Janowitz and Semir Beyaz and Guoqiang Wang and Sulan Xu and Bialkowska, {Agnieszka B.} and Luo, {Catherine K.} and Pin, {Christoph L.} and Guang Liang and Xiongbin Lu and Maoxin Wu and Shroyer, {Kenneth R.} and Wolff, {Robert A.} and William Plunkett and Baoan Ji and Zhaoshen Li and Ellen Li and Xiaokun Li and Yang, {Vincent W.} and Logsdon, {Craig D.} and Abbruzzese, {James L.} and Weiqin Lu",
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TY - JOUR

T1 - Oncogenic KRAS Reduces Expression of FGF21 in Acinar Cells to Promote Pancreatic Tumorigenesis in Mice on a High-Fat Diet

AU - Luo, Yongde

AU - Yang, Yaying

AU - Liu, Muyun

AU - Wang, Dan

AU - Wang, Feng

AU - Bi, Yawei

AU - Ji, Juntao

AU - Li, Suyun

AU - Liu, Yan

AU - Chen, Rong

AU - Huang, Haojie

AU - Wang, Xiaojie

AU - Swidnicka-Siergiejko, Agnieszka K.

AU - Janowitz, Tobias

AU - Beyaz, Semir

AU - Wang, Guoqiang

AU - Xu, Sulan

AU - Bialkowska, Agnieszka B.

AU - Luo, Catherine K.

AU - Pin, Christoph L.

AU - Liang, Guang

AU - Lu, Xiongbin

AU - Wu, Maoxin

AU - Shroyer, Kenneth R.

AU - Wolff, Robert A.

AU - Plunkett, William

AU - Ji, Baoan

AU - Li, Zhaoshen

AU - Li, Ellen

AU - Li, Xiaokun

AU - Yang, Vincent W.

AU - Logsdon, Craig D.

AU - Abbruzzese, James L.

AU - Lu, Weiqin

PY - 2019/11

Y1 - 2019/11

N2 - Background & Aims: Obesity is a risk factor for pancreatic cancer. In mice, a high-fat diet (HFD) and expression of oncogenic KRAS lead to development of invasive pancreatic ductal adenocarcinoma (PDAC) by unknown mechanisms. We investigated how oncogenic KRAS regulates the expression of fibroblast growth factor 21, FGF21, a metabolic regulator that prevents obesity, and the effects of recombinant human FGF21 (rhFGF21) on pancreatic tumorigenesis. Methods: We performed immunohistochemical analyses of FGF21 levels in human pancreatic tissue arrays, comprising 59 PDAC specimens and 45 nontumor tissues. We also studied mice with tamoxifen-inducible expression of oncogenic KRAS in acinar cells (KrasG12D/+ mice) and fElasCreERT mice (controls). KrasG12D/+ mice were placed on an HFD or regular chow diet (control) and given injections of rhFGF21 or vehicle; pancreata were collected and analyzed by histology, immunoblots, quantitative polymerase chain reaction, and immunohistochemistry. We measured markers of inflammation in the pancreas, liver, and adipose tissue. Activity of RAS was measured based on the amount of bound guanosine triphosphate. Results: Pancreatic tissues of mice expressed high levels of FGF21 compared with liver tissues. FGF21 and its receptor proteins were expressed by acinar cells. Acinar cells that expressed KrasG12D/+ had significantly lower expression of Fgf21 messenger RNA compared with acinar cells from control mice, partly due to down-regulation of PPARG expression—a transcription factor that activates Fgf21 transcription. Pancreata from KrasG12D/+ mice on a control diet and given injections of rhFGF21 had reduced pancreatic inflammation, infiltration by immune cells, and acinar-to-ductal metaplasia compared with mice given injections of vehicle. HFD-fed KrasG12D/+ mice given injections of vehicle accumulated abdominal fat, developed extensive inflammation, pancreatic cysts, and high-grade pancreatic intraepithelial neoplasias (PanINs); half the mice developed PDAC with liver metastases. HFD-fed KrasG12D/+ mice given injections of rhFGF21 had reduced accumulation of abdominal fat and pancreatic triglycerides, fewer pancreatic cysts, reduced systemic and pancreatic markers of inflammation, fewer PanINs, and longer survival—only approximately 12% of the mice developed PDACs, and none of the mice had metastases. Pancreata from HFD-fed KrasG12D/+ mice given injections of rhFGF21 had lower levels of active RAS than from mice given vehicle. Conclusions: Normal acinar cells from mice and humans express high levels of FGF21. In mice, acinar expression of oncogenic KRAS significantly reduces FGF21 expression. When these mice are placed on an HFD, they develop extensive inflammation, pancreatic cysts, PanINs, and PDACs, which are reduced by injection of FGF21. FGF21 also reduces the guanosine triphosphate binding capacity of RAS. FGF21 might be used in the prevention or treatment of pancreatic cancer.

AB - Background & Aims: Obesity is a risk factor for pancreatic cancer. In mice, a high-fat diet (HFD) and expression of oncogenic KRAS lead to development of invasive pancreatic ductal adenocarcinoma (PDAC) by unknown mechanisms. We investigated how oncogenic KRAS regulates the expression of fibroblast growth factor 21, FGF21, a metabolic regulator that prevents obesity, and the effects of recombinant human FGF21 (rhFGF21) on pancreatic tumorigenesis. Methods: We performed immunohistochemical analyses of FGF21 levels in human pancreatic tissue arrays, comprising 59 PDAC specimens and 45 nontumor tissues. We also studied mice with tamoxifen-inducible expression of oncogenic KRAS in acinar cells (KrasG12D/+ mice) and fElasCreERT mice (controls). KrasG12D/+ mice were placed on an HFD or regular chow diet (control) and given injections of rhFGF21 or vehicle; pancreata were collected and analyzed by histology, immunoblots, quantitative polymerase chain reaction, and immunohistochemistry. We measured markers of inflammation in the pancreas, liver, and adipose tissue. Activity of RAS was measured based on the amount of bound guanosine triphosphate. Results: Pancreatic tissues of mice expressed high levels of FGF21 compared with liver tissues. FGF21 and its receptor proteins were expressed by acinar cells. Acinar cells that expressed KrasG12D/+ had significantly lower expression of Fgf21 messenger RNA compared with acinar cells from control mice, partly due to down-regulation of PPARG expression—a transcription factor that activates Fgf21 transcription. Pancreata from KrasG12D/+ mice on a control diet and given injections of rhFGF21 had reduced pancreatic inflammation, infiltration by immune cells, and acinar-to-ductal metaplasia compared with mice given injections of vehicle. HFD-fed KrasG12D/+ mice given injections of vehicle accumulated abdominal fat, developed extensive inflammation, pancreatic cysts, and high-grade pancreatic intraepithelial neoplasias (PanINs); half the mice developed PDAC with liver metastases. HFD-fed KrasG12D/+ mice given injections of rhFGF21 had reduced accumulation of abdominal fat and pancreatic triglycerides, fewer pancreatic cysts, reduced systemic and pancreatic markers of inflammation, fewer PanINs, and longer survival—only approximately 12% of the mice developed PDACs, and none of the mice had metastases. Pancreata from HFD-fed KrasG12D/+ mice given injections of rhFGF21 had lower levels of active RAS than from mice given vehicle. Conclusions: Normal acinar cells from mice and humans express high levels of FGF21. In mice, acinar expression of oncogenic KRAS significantly reduces FGF21 expression. When these mice are placed on an HFD, they develop extensive inflammation, pancreatic cysts, PanINs, and PDACs, which are reduced by injection of FGF21. FGF21 also reduces the guanosine triphosphate binding capacity of RAS. FGF21 might be used in the prevention or treatment of pancreatic cancer.

KW - FGFR1

KW - Gene Regulation

KW - KLB

KW - Signaling

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